Despite the advent of mass chemotherapy programs, schistosomiasis remains a very significant cause of human disease in Africa, The Middle East, Asia and South America. Our long-term goal is to understand the protective mechanisms that allow host survival in the face of extensive tissue damage associated with chronic schistosomiasis. Work over the last 15 years has revealed that the nature of the CD4+ T cell response induced by egg antigens is critical in determining the death or survival outcome of infection. The infection induces a Th2 response, and the Th2 bias is critical, since in the absence of IL-4, a major product of Th2 cells, infected mice die rapidly after eggs begin to be produced by the parasites, due to an immunopathologic response in which NO and TNF (products of classically activated, M1 macrophages) are implicated. In contrast, infected wild type mice survive over long periods of time, thereby modeling the chronic nature of the disease in humans. In this model, as in humans, infection severity is linked to parasite burden (the more worm pairs a mouse is infected with, the more eggs it is exposed to, and the sicker it will be), and over time the repeated cycles of inflammation and resolution can lead to severe liver fibrosis, which again mirrors the most serious disease manifestation of human schistosomiasis. There is evidence that the protective mechanisms that permit host survival during schistosomiasis are mediated by cells that that can be categorized as alternatively activated (M2) macrophages, and that IgG1, which is made by B cells that have been helped by IL-4 producing T follicular helper (Tfh) cells, plays a role in this process during the later stages of disease. However, we have surprisingly little understanding of how these macrophage- and B cell-dependent mechanisms operate, and it is on these areas that our proposal focuses. We have two aims. Specific Aim 1 is to understand the role of the Tfh/B cell axis during infection. Here we will determine the evolution of the T cell and B cell responses over time during infection, incorporating a detailed study of Th2 cells, Tfh cells and plasma cells. We will ask whether both Th2 and Tfh responses are modulated over time, and whether increasing the relative output of Tfh cells vs. Th2 effector cells improves the prognosis during chronic schistosomiasis. We will ask how B cells get into the liver during schistosomiasis and explore the fate and function of the cells once they have infiltrated this organ. Specific Aim 2 is to establish the origin and function of hepatic macrophages during chronic infection. For this aim we will use new tools to explore the origin and role of macrophages in the hepatic tissues of chronically infected mice. We will ask whether the primary role of antibody is (in the form of immune complexes) to bind to Fc?RIIB on monocytes/macrophages and thereby inhibit inflammation during chronic schistosomiasis. We will determine how the absence of B cells influences the hepatic macrophage population and determine whether dysregulated thromboxane-A2 production by macrophages underlies the development of severe portal hypertension during chronic schistosomiasis in the absence of antibody.